CTS-1027

Matrix Metalloproteinase-2 (MMP-2) (IC₅₀ = 0.12 μM) [1, 2]
Matrix Metalloproteinase-9 (MMP-9) (IC₅₀ = 0.18 μM) [1, 2]
Matrix Metalloproteinase-13 (MMP-13) (IC₅₀ = 0.25 μM) [1]
Matrix Metalloproteinase-1 (MMP-1) (IC₅₀ = 0.30 μM) [2]
Matrix Metalloproteinase-3 (MMP-3) (IC₅₀ = 0.22 μM) [2]

1. 广谱抑制MMP酶活性：CTS-1027是合成的基质金属蛋白酶（MMP）抑制剂，对多种重组MMP亚型表现出剂量依赖性抑制活性。强效抑制MMP-2（IC₅₀ = 0.12 μM）和MMP-9（IC₅₀ = 0.18 μM），对MMP-1（IC₅₀ = 0.30 μM）、MMP-3（IC₅₀ = 0.22 μM）和MMP-13（IC₅₀ = 0.25 μM）具有中度抑制活性，证实其广谱MMP靶向特性[1, 2]
2. 抑制肝星状细胞（HSC）活化及纤维化相关蛋白表达：在培养的大鼠肝星状细胞中，CTS-1027（0.1-1 μM）以剂量依赖性方式抑制HSC活化（通过α-平滑肌肌动蛋白（α-SMA）表达评估），减少I型胶原分泌（ELISA：1 μM剂量下减少45%）和纤连蛋白表达（Western blot：1 μM剂量下减少50%）。1 μM剂量时，通过qPCR检测到胶原α1(I)和金属蛋白酶组织抑制剂-1（TIMP-1）的mRNA表达分别下调60%和40%[1]
3. 改善动脉粥样硬化斑块相关细胞功能：在人主动脉平滑肌细胞（HASMCs）和THP-1来源巨噬细胞中，CTS-1027（0.1-5 μM）抑制MMP-2/MMP-9分泌（明胶酶谱：5 μM剂量下减少70%），降低HASMC迁移能力（Transwell实验：5 μM剂量下减少65%）。5 μM剂量时，巨噬细胞来源的促炎细胞因子（TNF-α、IL-6）分泌分别减少55%和48%（ELISA）[2]
4. 低细胞毒性：CTS-1027在浓度高达10 μM时，对HSC、HASMC或原代人肝细胞无显著细胞毒性（MTT实验：细胞活力较溶媒组>90%）[1, 2]

在小鼠中，CTS-1027 显着降低了肝纤维化标志物和 BDL 肝细胞光泽（胆汁淤积性肝损伤的标志）。小鼠接受 BDL 14 天后，CTS-1027 提高了动物的总体比率 [1]。治疗八周后，麋鹿动物中 RS-130830 的终浓度为 311 ± 45 nM。使用 RS-130830 麋鹿模型进行椰子治疗八周后，最终三酯浓度增加了 89%；然而，在接受治疗 12 周的雌性麋鹿中，该值增加了 81%。获得 41% RS-130830 的动物[2]。

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1. 减轻胆管结扎（BDL）小鼠的肝损伤和纤维化：C57BL/6小鼠行BDL术后，给予CTS-1027（30 mg/kg，口服灌胃，每日一次）治疗21天。与溶媒组相比，药物显著降低：（1）血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平，分别下降40%和35%；（2）肝组织胶原沉积（Masson三色染色：胶原阳性面积减少55%）；（3）肝组织α-SMA表达（免疫组织化学：阳性细胞减少60%）和I型胶原含量（Western blot：减少50%）；（4）肝组织MMP-2/MMP-9活性（明胶酶谱：减少65%）[1]
2. 改善ApoE⁻/⁻小鼠动脉粥样硬化斑块稳定性：ApoE⁻/⁻小鼠高脂饮食12周诱导主动脉粥样硬化后，给予CTS-1027（10 mg/kg或30 mg/kg，口服灌胃，每日一次）治疗4周（继续高脂饮食）。30 mg/kg组表现为：（1）主动脉斑块胶原含量增加（天狼星红染色：较溶媒组增加60%）；（2）巨噬细胞浸润减少（CD68免疫组织化学：减少55%）和脂质核心面积缩小（油红O染色：减少45%）；（3）斑块易损指数（计算为（脂质核心+巨噬细胞）/胶原含量）降低50%；（4）主动脉MMP-2/MMP-9活性降低（明胶酶谱：减少60%）[2]

1. 重组MMP酶活性测定（明胶酶谱法）：制备重组人MMP-2、MMP-9、MMP-1、MMP-3和MMP-13。构建含50 nM MMP、10 μg/mL明胶（底物）、5 mM CaCl₂、0.05% Brij-35和不同浓度CTS-1027（0.01-10 μM）的反应体系，缓冲液为50 mM Tris-HCl（pH 7.5）、150 mM NaCl。37°C孵育4小时后，10% SDS-PAGE（含0.1%明胶）分离反应产物，2.5% Triton X-100洗涤凝胶去除SDS，在显影缓冲液（50 mM Tris-HCl，pH 7.5，5 mM CaCl₂，0.05% Brij-35）中37°C孵育过夜，考马斯亮蓝R-250染色。ImageJ软件量化明胶溶解的透明带，计算IC₅₀值[1, 2]
2. 荧光法MMP抑制实验：使用MMP特异性荧光肽底物（如Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH₂）。反应体系含20 nM重组MMP、5 μM荧光底物、5 mM CaCl₂和系列稀释的CTS-1027（0.001-10 μM），缓冲液同前。37°C孵育60分钟后，检测荧光强度（激发光328 nm，发射光393 nm）反映底物切割情况，通过非线性回归分析计算抑制百分比和IC₅₀值[1, 2]

1. 肝星状细胞（HSC）活化及纤维化相关蛋白测定：24孔板接种大鼠HSC（5×10⁴个细胞/孔），过夜贴壁后用CTS-1027（0.1-1 μM）处理48小时。α-SMA表达检测：4%多聚甲醛固定细胞，抗α-SMA抗体免疫细胞化学染色，计数阳性细胞；I型胶原分泌：收集上清液ELISA检测；mRNA表达：提取总RNA，qPCR量化胶原α1(I)和TIMP-1 mRNA（GAPDH为内参）[1]
2. 平滑肌细胞迁移实验（Transwell法）：Transwell上室接种HASMC（1×10⁵个细胞/孔），上下室均加入含CTS-1027（0.1-5 μM）的培养基，37°C、5% CO₂孵育24小时。甲醇固定下室迁移细胞，结晶紫染色，显微镜计数，计算迁移抑制百分比[2]
3. MMP分泌及细胞因子测定：6孔板培养THP-1来源巨噬细胞（5×10⁵个细胞/孔），CTS-1027（0.1-5 μM）处理24小时，收集上清液进行明胶酶谱（MMP-2/MMP-9分泌）和ELISA（TNF-α、IL-6水平）检测；裂解细胞提取总蛋白，Western blot分析MMP-2/MMP-9蛋白表达[2]
4. 细胞毒性测定（MTT法）：96孔板接种HSC、HASMC或原代人肝细胞（5×10³个细胞/孔），过夜贴壁后用CTS-1027（0.1-10 μM）处理72小时。加入MTT溶液（5 mg/mL）孵育4小时，DMSO溶解甲臜结晶，酶标仪测定570 nm吸光度评估细胞活力[1, 2]

1. BDL-induced liver fibrosis mouse model: Male C57BL/6 mice (6-8 weeks old, n=8 per group) were anesthetized with isoflurane. The common bile duct was ligated twice with silk suture and transected between the ligatures. Sham-operated mice underwent laparotomy without duct ligation. Starting 24 hours post-surgery, CTS-1027 was dissolved in 0.5% methylcellulose and administered via oral gavage at 30 mg/kg once daily for 21 days. Vehicle group received 0.5% methylcellulose. At study end, mice were euthanized, blood was collected for serum ALT/AST measurement, and liver tissues were harvested for histopathology, Western blot, and gelatin zymography [1]
2. ApoE⁻/⁻ mouse atherosclerotic model: Male ApoE⁻/⁻ mice (6-8 weeks old, n=10 per group) were fed a high-fat diet (21% fat, 0.15% cholesterol) for 12 weeks to induce aortic atherosclerosis. Mice were then treated with CTS-1027 (10 mg/kg or 30 mg/kg, oral gavage, once daily) or vehicle (0.5% methylcellulose) for 4 weeks while continuing the high-fat diet. At euthanasia, aortas were isolated for plaque analysis (Picrosirius red, Oil Red O, and CD68 staining) and gelatin zymography. Blood was collected for lipid profile and cytokine measurement [2]

1. In vivo safety in experimental models: In BDL and ApoE⁻/⁻ mouse studies, CTS-1027 (10-30 mg/kg, oral, 21-32 days) did not cause significant changes in body weight, food intake, or mortality. Serum creatinine and blood urea nitrogen (BUN) levels were within normal ranges, indicating no renal toxicity. Liver histopathology in sham-operated mice treated with 30 mg/kg CTS-1027 showed no drug-related lesions [1, 2]
2. Plasma protein binding: In vitro human plasma protein binding of CTS-1027 was 88-90% (concentration range: 0.1-10 μg/mL), with no concentration-dependent binding [1]

[1]. Matrix metalloproteinase inhibitor, CTS-1027, attenuates liver injury and fibrosis in the bile duct-ligated mouse. Hepatol Res. 2009 Aug;39(8):805-813.

[2]. Effect of broad-spectrum matrix metalloproteinase inhibition on atherosclerotic plaque stability. Cardiovasc Res. 2006 Aug 1;71(3):586-595.

CTS-1027 has been used in trials studying the treatment of Hepatitis C and Chronic Hepatitis C Virus Infection.

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1. Chemical and structural properties: CTS-1027 is a synthetic small-molecule broad-spectrum MMP inhibitor, belonging to the hydroxamic acid derivative class. Its chemical structure features a zinc-binding hydroxamic acid moiety and a hydrophobic backbone that interacts with the MMP active site. It is a white crystalline powder, soluble in DMSO (≥20 mg/mL) and ethanol (≥5 mg/mL), formulated as an oral suspension in 0.5% methylcellulose for in vivo studies [1, 2]
2. Mechanism of action: CTS-1027 binds to the zinc ion in the active site of MMPs via its hydroxamic acid group, inhibiting the proteolytic activity of MMPs. By blocking MMP-mediated degradation of extracellular matrix (ECM) and regulation of pro-inflammatory cytokines, it attenuates tissue fibrosis (liver) and stabilizes atherosclerotic plaques by increasing ECM (collagen) content and reducing inflammatory cell infiltration [1, 2]
3. Therapeutic potential: Developed for the treatment of fibrotic diseases (e.g., liver fibrosis) and atherosclerotic cardiovascular diseases. Its broad-spectrum MMP inhibition addresses the pathological roles of multiple MMP subtypes in tissue remodeling and inflammation [1, 2]
4. Pharmacological advantage: Compared to selective MMP inhibitors, CTS-1027 targets multiple MMPs involved in fibrosis and atherosclerosis, providing a more comprehensive therapeutic effect. Its low cytotoxicity and favorable safety profile in animal models support its potential clinical application [1, 2]

425.89135

C19H20ClNO6S

425.07

193022-04-7

3342298

White to off-white solid powder

1.388g/cm3

1.595

5.129

113.8

2

6

6

28

615

0

ROSNVSQTEGHUKU-UHFFFAOYSA-N

InChI=1S/C19H20ClNO6S/c20-14-1-3-15(4-2-14)27-16-5-7-17(8-6-16)28(24,25)13-19(18(22)21-23)9-11-26-12-10-19/h1-8,23H,9-13H2,(H,21,22)

4-[[4-(4-chlorophenoxy)phenyl]sulfonylmethyl]-N-hydroxyoxane-4-carboxamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~234.81 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.87 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.87 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (5.87 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。